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Alcohol effects on γ-aminobutyric acid type A receptors: Are extrasynaptic receptors the answer?

Department of Molecular and Medical Pharmacology, University of California Los Angeles, Room 23-338 CHS, 650 Charles Young Drive South, Los Angeles, CA 90095-1735, USA.
Life Sciences (Impact Factor: 2.3). 12/2004; 76(1):1-8. DOI: 10.1016/j.lfs.2004.05.035
Source: PubMed

ABSTRACT GABA(A) receptors have long been implicated in mediating at least part of the actions of ethanol in mammalian brain. However, until very recently, reports of the actions of EtOH on recombinant receptors have required very high doses of ethanol and animals lacking receptor subunits shown to be important for ethanol actions in vitro did not support the view that these subunits are crucial in ethanol actions. Recombinant alpha4beta3delta and alpha6beta3delta GABA(A) receptors are uniquely sensitive to ethanol, with a dose-response relationship mirroring the well known effects of alcohol consumption on the human brain. Receptors containing the delta subunit are thought to be located extrasynaptically and it will be important to determine if these extrasynaptic GABA(A) receptor subunit combinations mediate low dose alcohol effects in vivo.

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Available from: Martin Wallner, Aug 10, 2015
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    • "In cerebellar granule cells, acute EtOH robustly increases both tonic currents and phasic sIPSCs by increasing presynaptic Golgi cell firing, in part by inhibiting the Na + /K + -ATPase and depolarizing the membrane potential of Golgi cells (Botta et al., 2010; Diaz et al., 2013). It has been suggested that EtOH can also directly enhance a6-containing GABA A R function in cerebellar granule cells (Hanchar et al., 2004), but this has been a controversial finding (Baur et al., 2009; Botta et al., 2007). "
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    ABSTRACT: The central amygdala (CeA) has a unique role in integrating stress and the rewarding effects of ethanol (EtOH) and plays a major role in the development of EtOH dependence via signaling of corticotropin-releasing factor (CRF). A recent report by Herman and colleagues (2013) entitled "Novel Subunit-Specific Tonic GABA Currents and Differential Effects of Ethanol in the Central Amygdala of CRF Receptor-1 Reporter Mice" is the first study to investigate inhibitory tonic currents in relation to CRF signaling in the CeA. The findings of that study significantly enhance our understanding of inhibitory tonic currents in the CeA and give insight into how EtOH may differentially affect CRF signaling within the CeA, leading to the development of EtOH dependence. This commentary will focus on the recent findings of Herman and colleagues and will discuss the effects of EtOH on the entire anxiety/emotion circuitry.
    Alcoholism Clinical and Experimental Research 11/2013; 38(3). DOI:10.1111/acer.12298 · 3.31 Impact Factor
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    • "In particular, extrasynaptic GABA A R subtypes that contain the δ subunit (δ GABA A Rs) can be potentiated by ethanol concentrations as low as 3 mM; humans report feeling intoxicated at blood alcohol concentrations of 2 to 7 mM (Eckardt et al., 1998; Sundstrom-Poromaa et al., 2002; Wallner et al., 2003). Therefore, it is now thought that extrasynaptic δ GABA A Rs may play a crucial role in mediating the behavioral effects of ethanol (Hanchar et al., 2004). "
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    ABSTRACT: In recent years, the effect of ethanol on tonic inhibition mediated by extrasynaptic GABA(A) receptors (GABA(A)Rs) has become a topic of intensive investigation and some controversy. The high ethanol sensitivity of extrasynaptic GABA(A) receptors containing the δ subunit combined with the role of tonic inhibition in maintaining the background inhibitory "tone" in hippocampal circuits has suggested that they may play a key role mediating certain behavioral effects of ethanol, including those related to learning and memory. We have found that ethanol disrupts learning and learning-related hippocampal function more potently in adolescent animals than in adults and that ethanol promotes extrasynaptic receptor-mediated GABAergic tonic currents more potently in adolescents than in adults. However, there have been no studies of potential mechanisms that may underlie the enhanced ethanol sensitivity of the tonic current in adolescents. In this study, we recorded GABA(A) receptor-mediated tonic currents in dentate gyrus granule cells in hippocampal slices from adolescent and adult rats. As previously reported, we found that ethanol potentiated the currents more efficaciously in cells from adolescents than in those from adults. We also found that the GAT-1 blocker NO-711 eliminated this developmental difference in ethanol sensitivity. These findings suggest that regulation of ambient GABA by GABA transporters may contribute to the difference in ethanol sensitivity between adolescents and adults.
    Alcohol (Fayetteville, N.Y.) 05/2011; 45(6):577-83. DOI:10.1016/j.alcohol.2011.03.003 · 2.04 Impact Factor
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    • "Although GABA A Rs have for decades been implicated in EtOH actions (Liljequist and Engel, 1982; Suzdak et al., 1986), direct actions of relevant EtOH concentrations— defined as concentrations up to 30 mM, or slightly less than twice the legal driving limit— on classic synaptic GABA A Rs have been elusive (Wallner et al., 2006a). A possible solution for this conundrum was provided by findings that extrasynaptic ␦ subunit-containing GABA A Rs are enhanced by relevant low EtOH concentrations (Sundstrom-Poromaa et al., 2002; Wallner et al., 2003; Hanchar et al., 2004). Support for this hypothesis comes from the observation that a single nucleotide polymorphism in the ␣6 gene (␣6R100Q), initially identified in rats with increased alcohol-induced motor impairment (also known as alcohol nontolerant rats) (Uusi- Oukari and Korpi, 1989), further increases the EtOH sensitivity of ␣6␤3␦ receptors in vivo and in vitro (Hanchar et al., 2005). "
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    ABSTRACT: GABA(A) receptors (GABA(A)Rs) have long been a focus as targets for alcohol actions. Recent work suggests that tonic GABAergic inhibition mediated by extrasynaptic δ subunit-containing GABA(A)Rs is uniquely sensitive to ethanol and enhanced at concentrations relevant for human alcohol consumption. Ethanol enhancement of recombinant α4β3δ receptors is blocked by the behavioral alcohol antagonist 8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid ethyl ester (Ro15-4513), suggesting that EtOH/Ro15-4513-sensitive receptors mediate important behavioral alcohol actions. Here we confirm alcohol/alcohol antagonist sensitivity of α4β3δ receptors using human clones expressed in a human cell line and test the hypothesis that discrepant findings concerning the high alcohol sensitivity of these receptors are due to difficulties incorporating δ subunits into functional receptors. To track δ subunit incorporation, we used a functional tag, a single amino acid change (H68A) in a benzodiazepine binding residue in which a histidine in the δ subunit is replaced by an alanine residue found at the homologous position in γ subunits. We demonstrate that the δH68A substitution confers diazepam sensitivity to otherwise diazepam-insensitive α4β3δ receptors. The extent of enhancement of α4β3δH68A receptors by 1 μM diazepam, 30 mM EtOH, and 1 μM β-carboline-3-carboxy ethyl ester (but not 1 μM Zn(2+) block) is correlated in individual recordings, suggesting that δ subunit incorporation into recombinant GABA(A)Rs varies from cell to cell and that this variation accounts for the variable pharmacological profile. These data are consistent with the notion that δ subunit-incorporation is often incomplete in recombinant systems yet is necessary for high ethanol sensitivity, one of the features of native δ subunit-containing GABA(A)Rs.
    Molecular pharmacology 11/2010; 78(5):918-24. DOI:10.1124/mol.109.062687 · 4.12 Impact Factor
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